Acute toxic effects of areca nut on central nervous system and liver: A case report

Key Clinical Message Areca nut (AN) is an addictive substance widely used in different world regions. There are several side effects associated with the use of AN, which have already been reported. However, the reports on hepatotoxicity of AN are sporadic and non‐conclusive. In the present case report, we investigated the hepatotoxicity of AN in a four‐year‐old Iranian girl who was transferred to our medical center with abdominal pain, vomiting, diarrhea, fever, and other symptoms such as hematuria, decreased mental status, multiple seizure episodes. After a comprehensive evaluation, it was concluded that these signs and symptoms were all attributed to AN consumption, which was given by her mother to control diarrhea. Eventually, the patient medical conditions were managed successfully, and she survived by intense medical care. In conclusion, we suggest AN should be considered a potential hepatotoxic agent.


| BACKGROUND
Areca nut (AN) is consumed by 600 million people worldwide, and betel quid, a preparation containing AN, is consumed by 10%-20% of the world's population.The world's largest consumers of AN are India and other Southeast Asian countries. 1After nicotine, ethanol, and caffeine, AN is the most commonly used addictive substance globally.There is strong evidence that AN, whether with or without tobacco use, can cause cancer. 2According to the IARC, the AN is carcinogenic in humankind.It has been linked to cancers in different body areas such as the mouth, pharynx, esophagus, liver, bile ducts, and the uterus. 3This report describes a child's medical condition transferred to There are several side effects associated with the use of AN, which have already been reported.However, the reports on hepatotoxicity of AN are sporadic and non-conclusive.In the present case report, we investigated the hepatotoxicity of AN in a four-year-old Iranian girl who was transferred to our medical center with abdominal pain, vomiting, diarrhea, fever, and other symptoms such as hematuria, decreased mental status, multiple seizure episodes.After a comprehensive evaluation, it was concluded that these signs and symptoms were all attributed to AN consumption, which was given by her mother to control diarrhea.Eventually, the patient medical conditions were managed successfully, and she survived by intense medical care.In conclusion, we suggest AN should be considered a potential hepatotoxic agent.

K E Y W O R D S
an addictive substance, Areca nut, case report, hepatotoxic agent, hepatotoxicity our medical center with altered mental status, seizure, elevated hepatic transaminases, hematuria, and hemolysis associated with AN toxicity.

| CASE PRESENTATION
A four-year-old girl was referred to our hospital with hematuria and altered mental status, followed by frequent vomiting, diarrhea, and fever episodes.After talking to her mother, it was indicated that her general health status was excellent 2 days before her admission into the medical center.There was no remarkable health condition in her medical history.Her body weight was 12 kg.In the past 2 days, she developed a sudden abdominal pain, diarrhea, nausea, and three episodes of vomiting about 6 h after her meal.Before admission to the emergency department of Jahrom Hospital (Jahrom, Iran), she was given Ibuprofen syrup (3 mL) for her fever and AN (Figure 1) powder (two tablespoons) for her diarrhea by her mother.The patient's condition deteriorated immediately after AN ingestion.She developed a progressive paleness, and her extremities turned cold.She had blood in her urine (gross hematuria) and two episodes of generalized tonic-clonic seizure with an interval of 30 min.The duration of the first seizure episode was about 10 min, and the second episode lasted for 3 min.Eventually, she was brought to the ED of Jahrom hospital.During the initial evaluations in the ED, she was febrile, pale, and had tachycardia, gross hematuria, and non-exudative conjunctivitis.Her heart rate was 140 beats/min, and her respiratory rate was 40/min.Oxygen saturation was 85%, blood pressure was 90/50 mmHg, and her body temperature was 39.4°C.
Considering the patient's critical condition and lack of a PICU in Jahrom hospital, the medical team transferred her to Namazee Hospital, Shiraz, Iran.Due to high suspicion of a septic shock, intravenous hydration, and Vancomycin (15 mg/kg i.v.Q8H), and Ceftriaxone (100 mg/ kg i.v.Q6h) were empirically prescribed.The patient was promptly transferred to PICU with GCS 13/15.At the PICU, rigorous intravenous hydration and the administration of previous antibiotics continued, and acyclovir (10 mg/kg i.v.Q8h) was started to treat possible herpetic encephalitis.Additionally, after pediatric neurology consultation, an anticonvulsant, Levetiracetam (10 mg i.v.Q12h), was administered.
Further evaluations for neurological symptoms were conducted, including biochemical and microbiological examination of CSF and brain computed tomographic scan.The results of these tests were unremarkable.Electroencephalography showed some paroxysmal sharp waves, contrary to a simple febrile seizure.Thus, intravenous acyclovir was stopped after neurology consultation.
Initial laboratory results showed normal electrolyte levels except for hypokalemia, high values of CRP (>150 mg/L), LDH (3570 U/L), and fibrinogen (611 mg/ dL).Besides, the negative coombs' test and sufficient activity of G6PD all indicated non-immune hemolysis.Venous blood gas assessment included pH: 7.43, PCO 2 : 14.3 kPa, and HCO 3 : 9.6 mEq/L.Echocardiography was normal.Renal function tests were within the normal range (BUN 14 mg/dL, Creatinine 0.42 mg/dL), which ruled out the hemolytic uremic syndrome followed by Escherichia coli gastroenteritis.Elevated hepatic transaminases AST: 2670, ALT: 970 U/L, and INR: 1.76 were observed.Total and direct bilirubin: 0.7, 0.3 g/dL, and alkaline phosphatase: 296 IU/L were reported within the normal range.Urine analysis showed +4 blood and +2 albumin, which could be due to hemolysis and fever.There was +3 occult blood and a high white blood cell count in the stool examination.Virology investigations were negative for HBV, HCV, HAV, SARS-Cov-2, and HSV 1 and 2 (Table 1).
On the second day of PICU admission, 120 mL packed cells were transfused due to the decreased hemoglobin level (initial value: 10.2 g/dL, follow-up value: 9 g/dL).All the patient's signs and symptoms were alleviated gradually.On the sixth day of admission, the patient was transferred to the pediatric GI ward after stabilizing her vital signs, decreasing the levels of AST and ALT, and normal ABG and imaging.While she was admitted to the GI ward, T A B L E 1 Laboratory evaluation on the first and last days of admission (NC, not checked; NR, not reported).antibiotic therapy, and Levetiracetam administration were continued.Zinc Sulfate (10 mg, p.o. daily), ursodeoxycholic acid (130 mg p.o. BID), and folic acid (5 mg daily) were added to her treatment.Eventually, The patient was discharged in a stable situation.The laboratory tests were repeated after 1 month, and all the results were within the normal range.

| DISCUSSION AND CONCLUSION
AN is an addictive substance widely used in South and Southeast Asia and the Asia Pacific region, particularly among migrant communities in Africa, and North America. 4If consumed in large quantities, AN can cause acute toxic symptoms such as dyspnea, tachypnea, tachycardia, palpitations, hypotension, chest tightness, nausea, vomiting, dizziness, abdominal colic, and even myocardial infarction and coma; however, in the majority of cases, the effects are transient, and patients recover quickly. 6n the study reported by Sundqvist et al., the AN extract decreased cell survival and membrane integrity in a dosedependent manner.The ANs aqueous extract was highly cytotoxic and genotoxic and resulted in the formation of both DNA single-strand breaks and DNA protein crosslinks. 5Another study indicated that tumors could arise in the buccal mucosa after exposure to AN. 6 Furthermore, the AN showed cytotoxic effects on red blood cells, resulting in hemolysis, hematuria, and anemia. 7n addition to AN being carcinogenic to the oral cavity, pharynx, esophagus, liver, and uterus, numerous adverse effects on the entire body organs have been reported.AN causes euphoria, tachycardia, hypertension, GABA inhibition, and neuronal damage while not affecting concentration or memory.It results in hyperlipidemia, vasospasm, and cardiac arrhythmias, increasing the risk of myocardial ischemia.Chronic consumption of AN results in hypothyroidism, prostate hyperplasia, infertility, and vitamin D deficiency. 2 Additionally, AN has been shown to increase the rate of preterm birth and stillbirth in tobacco smoker women. 8Besides, in the review of Javed et al., obesity, increased waist circumference, elevated triacylglycerol level, metabolic syndrome, hyperglycemia, and Type 2 diabetes were reported as the side effects of AN. 9 In our current case report, hepatotoxicity was one of the clinical findings.Because of the patient's unstable hemodynamics, the hepatic shock was considered one of the differential diagnoses for elevated liver function.Various medical conditions cause hepatic shock, including hemorrhage, surgery, respiratory failure, infection, and chronic shock.Other causes include failure of microcirculation, a systemic inflammatory reaction, and adverse treatment effects in patients admitted into the intensive care unit. 10urthermore, Adediji et al. demonstrated that aqueous extract of AN changes the blood levels of ALT, ALP, and AST and has detrimental effects on the liver of adult Wistar rats. 11In other studies, the AN was reported to be hepatotoxic, causing both cholestatic and hepatocellular hepatic injury and increased blood transaminases and alkaline phosphatase. 12,13Considering the citation mentioned above, we propose that the observed elevation of liver enzymes in this case report is most likely due to both hepatic shock as a predisposing factor and the hepatotoxic effects of ANs.
Regarding the neurologic effects of the AN, it has been previously described that betel chewing causes widespread cortical desynchronization of the EEG, indicating a state of arousal, and betel nut-induced extrapyramidal syndrome has also been well documented. 14,15A betel nutinduced seizure was reported in another case report in a young male.The patient had no other neuroradiologic or precipitating factors, and full recovery was observed without medication after abstinence. 16Although these reports were in line with our observation of our patient, a recent study found that the social practice of chewing Areca catechu nuts was linked to fewer seizure episodes in people with epilepsy.This observation could be due to the nut's natural stimulant properties or other reasons. 17This inconsistency should be investigated in future studies.
AN should be considered a cytotoxic and hepatotoxic agent.The patient's health conditions improved relatively rapidly after AN toxicity.In this case report, we concluded that the observed signs and symptoms, including decreased mental status, seizure, increased liver enzymes, and hemolysis, were due to AN's ingestion.